OBJECTIVE: To determine the effect of central and peripheral leptin administration on food intake and energy expenditure in rhesus monkeys. RESULTS Four adult rhesus monkeys, cannulated in the left lateral cerebral ventricle, were studied during all phases of the experiment. The animals were allowed continuous access to food and water throughout the experiment and 24-hour food intake was measured daily. Indirect respiration calorimetry was used to determine energy expenditure. In the first phase of the study, food intake was measured following intracerebro-ventricular (ICV) injections of vehicle or three doses (500 ng, 2 g, 22 g) of leptin. Leptin administration resulted in a dose dependent decrease in food intake (p<0.05). Food intake decreased by an average of 36% at 500ng, 33% at 2 g, and 54% at 22 g of leptin compared to placebo. Energy expenditure was also measured at 500 ng and 22 g ICV doses of leptin. Energy expenditure was not different (p>0.10) between placebo and leptin at either dose or at any period of the day. Considering the expected decrease in thermic effect of feeding with a decrease in intake, leptin may have resulted in a slight increase in energy expenditure of less than 10%. In the second phase of the experiment, food intake was measured following IV injection of 3 mg of leptin. In this case, leptin did not alter food intake, despite increasing serum leptin levels by as much as one hundred fold. These results suggest that leptin is a potent inhibitor of food intake in rhesus monkeys, but this effect requires elevation of leptin concentrations in the cerebrospinal fluid or critical brain sites. The transport system for movement of leptin across the blood-brain barrier may limit the influence of circulating leptin on food intake in rhesus monkeys. FUTURE DIRECTIONS We plan to apply the methods used in this experiment to continue investigating the role leptin and other central-acting peptides play in regulating food intake and energy expenditure. We also plan to test these compounds for efficacy in treating obesity. KEY WORDS leptin, obesity, food intake, energy expenditure